Project Abstract The majority of patients afflicted with a T-cell lymphoma (TCL) will experience disease progression and ultimately succumb to their disease, as current therapies are rarely curative, and the underlying mechanisms driving TCL progression and chemotherapy resistance are poorly understood. We have demonstrated that antigen-presenting cells, particularly lymphoma-associated macrophages (LAM) are abundant constituents of the tumor microenvironment (TME) in TCL, and directly promote the growth and survival of primary TCL cells ex vivo. Blockade of the major histocompatibility complex (MHC), required for antigen presentation and T-cell activation, inhibits LAM-induced proliferation of malignant T cells. Conversely, direct stimulation of the T-cell receptor (TCR) on primary TCL cells culminates in the activation and upregulation of transcription factors that promote the growth and survival of conventional T cells, including the zinc-finger transcription factor GATA-3. We have recently shown that GATA-3 identifies a molecularly and clinically distinct subset of TCL that are highly resistant to chemotherapy. Genetic and pharmacologic loss-of-function (and gain-of-function) strategies further demonstrated that GATA-3 confers resistance to chemotherapy. Collectively, our preliminary data are consistent with the hypothesis that TCR signaling and GATA-3-dependent gene expression are exploited by malignant T cells and promote chemotherapy resistance. A paucity of TCL models amenable to genetic manipulation and pharmacologic in vivo studies has hampered further progress. Therefore, the extent to which antigenic stimulation and GATA-3-dependent gene expression promote T-cell lymphomagenesis and chemotherapy resistance within the native tumor microenvironment, and within the context of a genetic landscape resembling human TCL, remains uncertain. We have identified novel, and clinically achievable, therapeutic strategies targeting the TCR, and we aim to extend those earlier findings here using primary TCL cells and patient-derived xenografts (PDX). Our long-term goals are to understand the role of antigen- presenting cells, and other constituents of the TME, in promoting T-cell lymphomagenesis; to identify the lymphomagenic factors they provide, including those that are antigen, costimulatory, and cytokine receptor dependent; and to develop novel therapeutic strategies exploiting these vulnerabilities that will improve outcomes for patients afflicted with these NHL. Our overall objective here is to determine the mechanisms by which the TCR and GATA-3 promote T-cell lymphomagenesis in vivo. This will be achieved by addressing our central hypothesis that TCL progression, including resistance to chemotherapy, is regulated by TCR- and GATA-3-dependent transcriptional programs. This hypothesis is well grounded in our own preliminary data, and is entirely consistent with our current understanding of the genetic landscape and molecular pathogenesis of the TCL. We anticipate that the research proposed will provide a strong scientific rationale for novel therapeutic strategies that will ultimately be tested in well-designed clinical trials.